Misfolded and aggregating proteins

Misfolded and aggregating proteins represent a broad class of therapeutic targets characterized by the loss of a protein's native three-dimensional structure and its subsequent assembly into toxic oligomers or insoluble fibrils [1.2.4, 1.2.5]. This process is a hallmark of numerous 'proteinopathies,' including neurodegenerative diseases like Alzheimer's, Parkinson's, and ALS, as well as systemic conditions like transthyretin amyloidosis [1.3.1, 1.4.4]. In these diseases, proteins such as amyloid-beta, tau, alpha-synuclein, and transthyretin undergo conformational changes that lead to the formation of beta-sheet-rich aggregates, which disrupt cellular homeostasis, induce oxidative stress, and trigger neuroinflammation [1.2.2, 1.4.4]. Therapeutic strategies targeting these proteins include monoclonal antibodies designed to clear existing aggregates, pharmacological chaperones that stabilize the native state to prevent misfolding, and small molecules or antisense oligonucleotides that inhibit the aggregation process or reduce the production of the precursor protein [1.3.1, 1.3.5]. While several disease-modifying therapies have recently gained regulatory approval, challenges remain, including the potential for off-target effects on functional protein forms and the risk of inflammatory responses like amyloid-related imaging abnormalities (ARIA) [1.4.1, 1.4.3].

Other names

Protein aggregatesPathological protein aggregatesAmyloidogenic proteinsMisfolded proteinsProteotoxic aggregatesInclusion bodies

Therapeutic strategies include the stabilization of native protein states (thermodynamic approach), inhibition of the aggregation process (kinetic approach), promotion of aggregate clearance via autophagy or the proteasome, and immunotherapy-mediated removal of existing aggregates [1.3.1, 1.3.2, 1.3.5].